1. Field of the Invention
The present invention relates generally to mitochondrial disorders, and more specifically to the treatment of mitochondrial disorders by the administration of a pyrimidine-based nucleoside such as triacetyluridine.
2. Background Information
Mitochondrial diseases occur as inherited, sporadic, and acquired forms. Inherited forms of mitochondrial disease have a high mortality and morbidity. The most severe forms, such as Leigh syndrome (subacute necrotizing encephalomyelopathy) have a mortality of up to 50% per year after diagnosis. Multifactorial forms of mitochondrial disease include much more common disorders such as Huntington's disease, Parkinson's disease, Alzheimer's disease, and even certain forms of diabetes, heart disease, migraine, and stroke. Indeed the process of aging itself has been linked to progressive declines in mitochondrial function.
Mitochondrial diseases are defined as disorders of mitochondrial metabolism that arise from a genetic defect in nuclear or mitochondrial DNA. These may be maternally inherited, inherited as conventional Mendelian disorders, or acquired as new somatic mutations. The disorders may be manifested at any genetic level, from DNA and RNA, to protein. They may affect mitochondrial DNA replication, transcription, the transport of macromolecules into or out of mitochondria, or the function of macromolecules at their site of action within mitochondria. Historically, discussions of pathogenesis in mitochondrial disease have focused on the degradative (oxidative) functions of mitochondria. However, a number of the symptoms of mitochondrial disease may be related to essential biosynthetic (non-degradative) functions of the organelles that are often overlooked. One biosynthetic function of mitochondria is the synthesis of uridine.
Patients with a variety of different mitochondrial disorders may be functionally deficient in uridine because the rate-limiting step in de novo pyrimidine synthesis (Dihydroorotate CoQ Oxidoreductase, EC 1.3.99.11) is located on the inner membrane of mitochondria and coupled to the electron transport chain. Cells with mitochondrial dysfunction in culture are known to be dependent on exogenous uridine for growth and survival because of a functional deficiency in the activity of DHO-QO.
The epidemiology of the inherited forms of mitochondrial disease is largely unknown. It has been estimated that between 1 in 4000 and 1 in 1000 live births in the U.S. will be diagnosed with a mitochondrial disease before the age of 10 years. This is roughly comparable to the incidence of childhood cancer. Degenerative disorders of aging in which mitochondria play a role are, of course, much more common, affecting as many as 20-85 million Americans. Despite the wide-ranging effects of mitochondrial disorders, there is no currently accepted treatment methodology for addressing a problem of such significance and magnitude.
Accordingly, there is still a need in the art for a method for treating mitochondrial disorders, as a class.